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Abstract:

This invention relates to novel substituted pyridinones, their
derivatives, pharmaceutically acceptable salts, solvates, and hydrates
thereof. This invention also provides compositions comprising a compound
of this invention and the use of such compositions in methods of treating
diseases and conditions that are beneficially treated by administering a
TNF (tumor necrosis factor)-alpha production inhibitor/TGF (transforming
growth factor)-beta inhibitor.

[0002] The entire teaching of the above applications are incorporated
herein by reference.

BACKGROUND OF THE INVENTION

[0003] Pirfenidone, also known as 5-methyl-1-phenylpyridin-2(1H)-one, is
thought to inhibit collagen synthesis, down-regulate multiple cytokine
production, and block fibroblast proliferation and stimulation in
response to cytokines.

[0004] Pirfenidone is currently pre-registered for idiopathic pulmonary
fibrosis (IPF) in Japan, and is in clinical trials for IPF in Europe and
the US. It is also being investigated for neurofibromatosis,
Hermansky-Pudlak syndrome, diabetic nephropathy, renal failure,
hypertrophic cardiomyopathy (HCM), glomerulosclerosis (FSGS),
radiation-induced fibrosis, multiple sclerosis, and uterine leiomyomas
(fibroids).

[0006] This invention relates to novel substituted pyridinones, their
derivatives, pharmaceutically acceptable salts, solvates, and hydrates
thereof. This invention also provides compositions comprising a compound
of this invention and the use of such compositions in methods of treating
diseases and conditions that are beneficially treated by administering a
TNF (tumor necrosis factor)-alpha production inhibitor and/or TGF
(transforming growth factor)-beta inhibitor.

BRIEF DESCRIPTION OF THE DRAWINGS

[0007] FIG. 1 depicts the pharmacokinetics of a compound of this invention
as compared to pirfenidone following intravenous administration in rats.

[0008]FIG. 2 depicts the pharmacokinetics of a compound of this invention
as compared to pirfenidone following oral administration in rats.

[0009]FIG. 3 depicts the pharmacokinetics of compounds of this invention
as compared to pirfenidone following intravenous administration in
chimps.

[0010]FIG. 4 depicts the pharmacokinetics of compounds of this invention
as compared to pirfenidone following oral administration in chimps.

[0011]FIG. 5 depicts the pharmacokinetics of a compound of this invention
as compared to pirfenidone following intravenous administration in rats.

[0012]FIG. 6 depicts the pharmacokinetics of a compound of this invention
as compared to pirfenidone following intravenous administration in rats.

[0013]FIG. 7 depicts the pharmacokinetics of a compound of this invention
as compared to pirfenidone following oral administration in rats.

[0014]FIG. 8 depicts the pharmacokinetics of a compound of this invention
as compared to pirfenidone following oral administration in rats.

DETAILED DESCRIPTION OF THE INVENTION

[0015] The terms "ameliorate" and "treat" are used interchangeably and
include both therapeutic and prophylactic treatment. Both terms mean
decrease, suppress, attenuate, diminish, arrest, or stabilize the
development or progression of a disease (e.g., a disease or disorder
delineated herein), lessen the severity of the disease or improve the
symptoms associated with the disease.

[0016] "Disease" means any condition or disorder that damages or
interferes with the normal function of a cell, tissue, or organ.

[0017] It will be recognized that some variation of natural isotopic
abundance occurs in a synthesized compound depending upon the origin of
chemical materials used in the synthesis. Thus, a preparation of
pirfenidone will inherently contain small amounts of deuterated
isotopologues. The concentration of naturally abundant stable hydrogen
and carbon isotopes, notwithstanding this variation, is small and
immaterial as compared to the degree of stable isotopic substitution of
compounds of this invention. See, for instance, Wada E et al., Seikagaku
1994, 66:15; Ganes L Z et al., Comp Biochem Physiol Mol Integr Physiol
1998, 119:725. In a compound of this invention, when a particular
position is designated as having deuterium, it is understood that the
abundance of deuterium at that position is substantially greater than the
natural abundance of deuterium, which is 0.015%. A position designated as
having deuterium typically has a minimum isotopic enrichment factor of at
least 3000 (45% deuterium incorporation).

[0018] Unless otherwise stated, when a position is designated specifically
as "H" or "hydrogen", the position is understood to have hydrogen at its
natural abundance isotopic composition.

[0019] The term "isotopic enrichment factor" as used herein means the
ratio between the isotopic abundance of D at a specified position in a
compound of this invention and the naturally occurring abundance of that
isotope. The natural abundance of deuterium is 0.015%.

[0020] In one embodiment, each position designated specifically as "D" or
"deuterium" has an isotopic enrichment factor of at least 3340 (at least
50.1% incorporation of deuterium at that position). Thus, the resulting
compound has an isotopic enrichment factor of at least 3340.

[0021] In other embodiments, a compound of this invention has an isotopic
enrichment factor for each deuterium present at a site designated as a
potential site of deuteration on the compound of at least 3500 (52.5%
deuterium incorporation), at least 4000 (60% deuterium incorporation), at
least 4500 (67.5% deuterium incorporation), at least 5000 (75%
deuterium), at least 5500 (82.5% deuterium incorporation), at least 6000
(90% deuterium incorporation), at least 6333.3 (95% deuterium
incorporation), at least 6466.7 (97% deuterium incorporation), at least
6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium
incorporation). It is understood that the isotopic enrichment factor of
each deuterium present at a site designated as a site of deuteration is
independent of other deuterated sites. For example, if there are two
sites of deuteration on a compound one site could be deuterated at 52.5%
while the other could be deuterated at 75%. The resulting compound would
be considered to be a compound wherein the isotopic enrichment factor is
at least 3500 (52.5%).

[0022] The term "isotopologue" refers to a species that differs from a
specific compound of this invention only in the isotopic composition
thereof. Isotopologues can differ in the level of isotopic enrichment at
one or more positions and/or in the positions(s) of isotopic enrichment.

[0023] The term "compound," when referring to the compounds of the
invention, refers to a collection of molecules having an identical
chemical structure, except that there may be isotopic variation among the
constituent atoms of the molecules. Thus, it will be clear to those of
skill in the art that a compound represented by a particular chemical
structure containing indicated deuterium atoms, will also contain minor
amounts of isotopologues having hydrogen atoms at one or more of the
designated deuterium positions in that structure. The relative amount of
such isotopologues in a compound of this invention will depend upon a
number of factors including the isotopic purity of deuterated reagents
used to make the compound and the efficiency of incorporation of
deuterium in the various synthesis steps used to prepare the compound.
However, as set forth above, typically the relative amount of such
isotopologues in toto will be less than 55% of the amount of the compound
(i.e., the particular structure depicted will represent at least 45% of
the isotopologues that make up the compound). In other embodiments, the
relative amount of such isotopologues in toto will be less than 49.9%,
less than 47.5%, less than 40%, less than 32.5%, less than 25%, less than
17.5%, less than 10%, less than 5%, less than 3%, less than 1%, or less
than 0.5% of the compound.

[0024] The invention also includes solvates and hydrates of the present
invention.

[0025] A salt of a compound of this invention is formed between an acid
and a basic group of the compound, such as an amino functional group, or
a base and an acidic group of the compound, such as a carboxyl functional
group. According to another embodiment, the compound is a
pharmaceutically acceptable acid addition salt.

[0026] The term "pharmaceutically acceptable," as used herein, refers to a
component that is, within the scope of sound medical judgment, suitable
for use in contact with the tissues of humans and other mammals without
undue toxicity, irritation, allergic response and the like, and are
commensurate with a reasonable benefit/risk ratio. A "pharmaceutically
acceptable salt" means any non-toxic salt that, upon administration to a
recipient, is capable of providing, either directly or indirectly, a
compound of this invention. A "pharmaceutically acceptable counterion" is
an ionic portion of a salt that is not toxic when released from the salt
upon administration to a recipient.

[0028] As used herein, the term "hydrate" means a compound which further
includes a stoichiometric or non-stoichiometric amount of water bound by
non-covalent intermolecular forces. Examples of specific hydrates include
those hydrates that are known to form with respect to the non-deuterated
versions of the present compounds.

[0029] As used herein, the term "solvate" means a compound which further
includes a stoichiometric or non-stoichiometric amount of solvent such as
water, acetone, ethanol, methanol, dichloromethane, 2-propanol, or the
like, bound by non-covalent intermolecular forces. Examples of specific
solvates include those hydrates that are known to form with respect to
the non-deuterated versions of the present compounds.

[0030] The term "stable compounds," as used herein, refers to compounds
which possess stability sufficient to allow for their manufacture and
which maintain the integrity of the compound for a sufficient period of
time to be useful for the purposes detailed herein (e.g., formulation
into therapeutic products, intermediates for use in production of
therapeutic compounds, isolatable or storable intermediate compounds,
treating a disease or condition responsive to therapeutic agents).

[0031] "D" refers to deuterium. "Stereoisomer" refers to both enantiomers
and diastereomers. "Tert", "t", and "t-" each refer to tertiary.

[0032] Throughout this specification, a variable may be referred to
generally (e.g., "each R") or may be referred to specifically (e.g.,
R1, R2, R3, etc.). Unless otherwise indicated, when a
variable is referred to generally, it is meant to include all specific
embodiments of that particular variable.

Therapeutic Compounds

[0033] The present invention provides a compound of Formula I:

##STR00001##

or a pharmaceutically acceptable salt, hydrate or solvate thereof,
wherein:

[0034] ring A is a phenyl ring having zero to five deuterium;

[0035] each of R1, R2 and R3 is independently selected from
H or D; and

[0036] Y is selected from CH2D, CHD2, or CD3, and when at
least one of R1, R2, or R3 is D, or when ring A has at
least one deuterium, Y is additionally selected from CH3.

[0037] In one embodiment, the invention provides a compound wherein Y is
selected from CH2D, CHD2, or CD3.

[0038] One embodiment provides a compound of Formula I wherein ring A has
zero or five deuterium.

[0039] Another embodiment provides a compound of Formula I wherein Y is
CH3 or CD3.

[0040] Another embodiment provides a compound of Formula I wherein Y is
CD3 and ring A has zero or five deuterium.

[0041] Another embodiment provides a compound of Formula I wherein Y is
CD3 and ring A has zero deuterium.

[0042] In yet another embodiment, the compound is selected from any one of
the following:

##STR00002## ##STR00003##

[0043] In another set of embodiments, any atom not designated as deuterium
in any of the embodiments set forth above is present at its natural
isotopic abundance.

[0045] Such methods can be carried out utilizing corresponding deuterated
and optionally, other isotope-containing reagents and/or intermediates to
synthesize the compounds delineated herein, or invoking standard
synthetic protocols known in the art for introducing isotopic atoms to a
chemical structure. Certain intermediates can be used with or without
purification (e.g., filtration, distillation, sublimation,
crystallization, trituration, solid phase extraction, and
chromatography).

Exemplary Synthesis

##STR00004##

[0047] A convenient general method for synthesizing compounds of Formula I
is depicted in Scheme 1. An appropriately deuterated aminopyridine 10 is
oxidized to the corresponding pyridinone 11. The pyridinone 11 is then
combined with an appropriately deuterated iodobenzene 12 to produce a
compound of Formula I.

##STR00005##

[0048] Scheme 2 shows a route for making a deuterated aminopyridine
10-d3 useful in Scheme 1, wherein R1, R2, and R3 are
H; and Y is CD3. The scheme follows the general method set forth in
Japanese Patent publication JP2005255560. Commercially-available
3-(methyl-d3)-pyridine (13) is oxidized to the corresponding N-oxide
14, which is then be converted to aminopyridine 10-d3 via the
general method disclosed in German Patent publication DE4232175.
Alternatively, 3-(methyl-d3)-pyridine (13) may be treated with
n-BuNH2, followed by HBr to produce deuterated amino pyridine
10-d3 following the method disclosed in U.S. Pat. No. 4,405,790.

##STR00006##

[0049] Scheme 3 shows a route for making deuterated aminopyridine
10-d6 that is useful in Scheme 1, wherein R1, R2, and
R3 are D; and Y is CD3. The phenyl hydrogens in commercially
available 2-amino-5-methylpyridine (15) are catalytically exchanged for
deuteriums using activated Pd/C and D2O to produce 10-d6. See H
Esaki, et al, Tetrahedron 2006, 62:10954-10961.

##STR00007##

[0050] Scheme 4 shows various reactions for the direct deuteration of
pirfenidone (16) via H/D exchange under different conditions to provide
different compounds of Formula I. Treatment of 16 with NaOD in
D2O/CD3OD produces a compound of Formula I, wherein ring A
contains no deuterium; R1, and R2 are H; Y is CH3; and
R3 is D. Treatment of 16 with DCl in D2O in a microwave reactor
at 170° C. produces a compound of Formula I wherein ring A
contains no deuterium; R1 is D, R2 and R3 are H, and Y is
CH3. Treatment of 16 with 10% palladium on carbon in the presence of
H2 and D2O following the general methods of H Esaki, et al,
Tetrahedron 2006, 62:10954-10961 produces a compound of Formula I wherein
ring A contains no deuterium; R1 and R3 are D; R2 is H;
and Y is CD3.

##STR00008##

[0051] Scheme 5 shows an alternate route for producing a compound of
Formula I, wherein Y is CD3 and each of R1, R2 and R3
is hydrogen. Commercially available
6-oxo-1,6-dihydropyridine-3-carbonitrile (17) and sodium dodecyl sulfate
("SDS") and sulfuric acid are dissolved in n-butanol/water and
hydrogenated with deuterium gas over palladium on carbon to produce
5-(methyl-d3)-pyridin-2(1H)-one 18. The use of deuterated solvents
and reagents, such as D2SO4, nBuOD and D2O, provides 18 in
which the isotopic abundance is improved. The pyridinone 18 is then
treated with iodobenzene, copper (I) iodide, N,N'-dimethylethylenediamine
and K3PO4 to produce a compound of Formula I, wherein Y is
CD3; and each of R1, R2 and R3 is hydrogen. In Scheme
5, PhI may also represent a deuterated version of iodobenzene.

[0052] Yet another way of producing 5-(methyl-d3)-pyridin-2(1H)-one
18, and a compound of Formula I wherein Y is CD3, is set forth in
Example 6.

[0053] The specific approaches and compounds shown above are not intended
to be limiting. The chemical structures in the schemes herein depict
variables that are hereby defined commensurately with chemical group
definitions (moieties, atoms, etc.) of the corresponding position in the
compound formulae herein, whether identified by the same variable name
(i.e., R1, R2, R3, etc.) or not. The suitability of a
chemical group in a compound structure for use in the synthesis of
another compound is within the knowledge of one of ordinary skill in the
art.

[0054] Additional methods of synthesizing compounds of Formula I and their
synthetic precursors, including those within routes not explicitly shown
in schemes herein, are within the means of chemists of ordinary skill in
the art. Methods for optimizing reaction conditions and, if necessary,
minimizing competing by-products, are known in the art. Synthetic
chemistry transformations and protecting group methodologies (protection
and deprotection) useful in synthesizing the applicable compounds are
known in the art and include, for example, those described in Larock R,
Comprehensive Organic Transformations, VCH Publishers (1989); Greene T W
et al., Protective Groups in Organic Synthesis, 3rd Ed., John Wiley
and Sons (1999); Fieser L et al., Fieser and Fieser's Reagents for
Organic Synthesis, John Wiley and Sons (1994); and Paquette L, ed.,
Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons
(1995) and subsequent editions thereof.

[0055] Combinations of substituents and variables envisioned by this
invention are only those that result in the formation of stable
compounds.

Compositions

[0056] The invention also provides pyrogen-free compositions comprising an
effective amount of a compound of Formula I (e.g., including any of the
formulae herein), or a pharmaceutically acceptable salt, solvate, or
hydrate of said compound; and an acceptable carrier. Preferably, a
composition of this invention is formulated for pharmaceutical use ("a
pharmaceutical composition"), wherein the carrier is a pharmaceutically
acceptable carrier. The carrier(s) are "acceptable" in the sense of being
compatible with the other ingredients of the formulation and, in the case
of a pharmaceutically acceptable carrier, not deleterious to the
recipient thereof in an amount used in the medicament.

[0058] If required, the solubility and bioavailability of the compounds of
the present invention in pharmaceutical compositions may be enhanced by
methods well-known in the art. One method includes the use of lipid
excipients in the formulation. See "Oral Lipid-Based Formulations:
Enhancing the Bioavailability of Poorly Water-Soluble Drugs (Drugs and
the Pharmaceutical Sciences)," David J Hauss, ed. Informa Healthcare,
2007; and "Role of Lipid Excipients in Modifying Oral and Parenteral Drug
Delivery: Basic Principles and Biological Examples," Kishor M Wasan, ed.
Wiley-Interscience, 2006.

[0059] Another known method of enhancing bioavailability is the use of an
amorphous form of a compound of this invention optionally formulated with
a poloxamer, such as LUTROL® and PLURONIC® (BASF Corporation), or
block copolymers of ethylene oxide and propylene oxide. See U.S. Pat. No.
7,014,866; and United States patent publications 20060094744 and
20060079502.

[0060] The pharmaceutical compositions of the invention include those
suitable for oral, rectal, nasal, topical (including buccal and
sublingual), vaginal or parenteral (including subcutaneous,
intramuscular, intravenous and intradermal) administration. In certain
embodiments, the compound of the formulae herein is administered
transdermally (e.g., using a transdermal patch or iontophoretic
techniques). Other formulations may conveniently be presented in unit
dosage form, e.g., tablets, sustained release capsules, and in liposomes,
and may be prepared by any methods well known in the art of pharmacy.
See, for example, Remington's Pharmaceutical Sciences, Mack Publishing
Company, Philadelphia, Pa. (17th ed. 1985).

[0061] Such preparative methods include the step of bringing into
association with the molecule to be administered ingredients such as the
carrier that constitutes one or more accessory ingredients. In general,
the compositions are prepared by uniformly and intimately bringing into
association the active ingredients with liquid carriers, liposomes or
finely divided solid carriers, or both, and then, if necessary, shaping
the product.

[0062] In certain embodiments, the compound is administered orally.
Compositions of the present invention suitable for oral administration
may be presented as discrete units such as capsules, sachets, or tablets
each containing a predetermined amount of the active ingredient; a powder
or granules; a solution or a suspension in an aqueous liquid or a
non-aqueous liquid; an oil-in-water liquid emulsion; a water-in-oil
liquid emulsion; packed in liposomes; or as a bolus, etc. Soft gelatin
capsules can be useful for containing such suspensions, which may
beneficially increase the rate of compound absorption.

[0063] In the case of tablets for oral use, carriers that are commonly
used include lactose and corn starch. Lubricating agents, such as
magnesium stearate, are also typically added. For oral administration in
a capsule form, useful diluents include lactose and dried cornstarch.
When aqueous suspensions are administered orally, the active ingredient
is combined with emulsifying and suspending agents. If desired, certain
sweetening and/or flavoring and/or coloring agents may be added.

[0064] Compositions suitable for oral administration include lozenges
comprising the ingredients in a flavored basis, usually sucrose and
acacia or tragacanth; and pastilles comprising the active ingredient in
an inert basis such as gelatin and glycerin, or sucrose and acacia.

[0065] Compositions suitable for parenteral administration include aqueous
and non-aqueous sterile injection solutions which may contain
anti-oxidants, buffers, bacteriostats and solutes which render the
formulation isotonic with the blood of the intended recipient; and
aqueous and non-aqueous sterile suspensions which may include suspending
agents and thickening agents. The formulations may be presented in
unit-dose or multi-dose containers, for example, sealed ampules and
vials, and may be stored in a freeze dried (lyophilized) condition
requiring only the addition of the sterile liquid carrier, for example
water for injections, immediately prior to use. Extemporaneous injection
solutions and suspensions may be prepared from sterile powders, granules
and tablets.

[0066] Such injection solutions may be in the form, for example, of a
sterile injectable aqueous or oleaginous suspension. This suspension may
be formulated according to techniques known in the art using suitable
dispersing or wetting agents (such as, for example, Tween 80) and
suspending agents. The sterile injectable preparation may also be a
sterile injectable solution or suspension in a non-toxic
parenterally-acceptable diluent or solvent, for example, as a solution in
1,3-butanediol. Among the acceptable vehicles and solvents that may be
employed are mannitol, water, Ringer's solution and isotonic sodium
chloride solution. In addition, sterile, fixed oils are conventionally
employed as a solvent or suspending medium. For this purpose, any bland
fixed oil may be employed including synthetic mono- or diglycerides.
Fatty acids, such as oleic acid and its glyceride derivatives are useful
in the preparation of injectables, as are natural
pharmaceutically-acceptable oils, such as olive oil or castor oil,
especially in their polyoxyethylated versions. These oil solutions or
suspensions may also contain a long-chain alcohol diluent or dispersant.

[0067] The pharmaceutical compositions of this invention may be
administered in the form of suppositories for rectal administration.
These compositions can be prepared by mixing a compound of this invention
with a suitable non-irritating excipient which is solid at room
temperature but liquid at the rectal temperature and therefore will melt
in the rectum to release the active components. Such materials include,
but are not limited to, cocoa butter, beeswax and polyethylene glycols.

[0068] The pharmaceutical compositions of this invention may be
administered by nasal aerosol or inhalation. Such compositions are
prepared according to techniques well-known in the art of pharmaceutical
formulation and may be prepared as solutions in saline, employing benzyl
alcohol or other suitable preservatives, absorption promoters to enhance
bioavailability, fluorocarbons, and/or other solubilizing or dispersing
agents known in the art. See, e.g.: Rabinowitz J D and Zaffaroni A C,
U.S. Pat. No. 6,803,031, assigned to Alexza Molecular Delivery
Corporation.

[0069] Topical administration of the pharmaceutical compositions of this
invention is especially useful when the desired treatment involves areas
or organs readily accessible by topical application. For topical
application topically to the skin, the pharmaceutical composition should
be formulated with a suitable ointment containing the active components
suspended or dissolved in a carrier. Carriers for topical administration
of the compounds of this invention include, but are not limited to,
mineral oil, liquid petroleum, white petroleum, propylene glycol,
polyoxyethylene polyoxypropylene compound, emulsifying wax, and water.
Alternatively, the pharmaceutical composition can be formulated with a
suitable lotion or cream containing the active compound suspended or
dissolved in a carrier. Suitable carriers include, but are not limited
to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax,
cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water. The
pharmaceutical compositions of this invention may also be topically
applied to the lower intestinal tract by rectal suppository formulation
or in a suitable enema formulation. Topically-transdermal patches and
iontophoretic administration are also included in this invention.

[0070] Application of the subject therapeutics may be local, so as to be
administered at the site of interest. Various techniques can be used for
providing the subject compositions at the site of interest, such as
injection, use of catheters, trocars, projectiles, pluronic gel, stents,
sustained drug release polymers or other device which provides for
internal access.

[0071] Thus, according to yet another embodiment, the compounds of this
invention may be incorporated into compositions for coating an
implantable medical device, such as prostheses, artificial valves,
vascular grafts, stents, or catheters. Suitable coatings and the general
preparation of coated implantable devices are known in the art and are
exemplified in U.S. Pat. Nos. 6,099,562; 5,886,026; and 5,304,121. The
coatings are typically biocompatible polymeric materials such as a
hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene
glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof.
The coatings may optionally be further covered by a suitable topcoat of
fluorosilicone, polysaccharides, polyethylene glycol, phospholipids or
combinations thereof to impart controlled release characteristics in the
composition. Coatings for invasive devices are to be included within the
definition of pharmaceutically acceptable carrier, adjuvant or vehicle,
as those terms are used herein.

[0072] According to another embodiment, the invention provides a method of
coating an implantable medical device comprising the step of contacting
said device with the coating composition described above. It will be
obvious to those skilled in the art that the coating of the device will
occur prior to implantation into a mammal.

[0073] According to another embodiment, the invention provides a method of
impregnating an implantable drug release device comprising the step of
contacting said drug release device with a compound or composition of
this invention. Implantable drug release devices include, but are not
limited to, biodegradable polymer capsules or bullets, non-degradable,
diffusible polymer capsules and biodegradable polymer wafers.

[0074] According to another embodiment, the invention provides an
implantable medical device coated with a compound or a composition
comprising a compound of this invention, such that said compound is
therapeutically active.

[0075] According to another embodiment, the invention provides an
implantable drug release device impregnated with or containing a compound
or a composition comprising a compound of this invention, such that said
compound is released from said device and is therapeutically active.

[0076] Where an organ or tissue is accessible because of removal from the
patient, such organ or tissue may be bathed in a medium containing a
composition of this invention, a composition of this invention may be
painted onto the organ, or a composition of this invention may be applied
in any other convenient way.

[0077] In another embodiment, a composition of this invention further
comprises a second therapeutic agent. The second therapeutic agent may be
selected from any compound or therapeutic agent known to have or that
demonstrates advantageous properties when administered with a compound
having the same mechanism of action as pirfenidone. Such agents include
those indicated as being useful in combination with pirfenidone,
including but not limited to, those described in WO 2004019863, WO
2004105684, WO 2005013917, WO 2005038056, and WO 2005110478.

[0079] In another embodiment, the invention provides separate dosage forms
of a compound of this invention and one or more of any of the
above-described second therapeutic agents, wherein the compound and
second therapeutic agent are associated with one another. The term
"associated with one another" as used herein means that the separate
dosage forms are packaged together or otherwise attached to one another
such that it is readily apparent that the separate dosage forms are
intended to be sold and administered together (within less than 24 hours
of one another, consecutively or simultaneously).

[0080] In the pharmaceutical compositions of the invention, the compound
of the present invention is present in an effective amount. As used
herein, the term "effective amount" refers to an amount which, when
administered in a proper dosing regimen, is sufficient to treat
(therapeutically or prophylactically) the target disorder. For example,
to reduce or ameliorate the severity, duration or progression of the
disorder being treated, prevent the advancement of the disorder being
treated, cause the regression of the disorder being treated, or enhance
or improve the prophylactic or therapeutic effect(s) of another therapy.

[0081] The interrelationship of dosages for animals and humans (based on
milligrams per meter squared of body surface) is described in Freireich
et al., (1966) Cancer Chemother Rep 50: 219. Body surface area may be
approximately determined from height and weight of the patient. See,
e.g., Scientific Tables, Geigy Pharmaceuticals, Ardsley, N.Y., 1970, 537.

[0082] In one embodiment, an effective amount of a compound of this
invention can range from about 2 to about 8000 mg per treatment. In more
specific embodiments the range is from about 20 to 4000 mg or from 40 to
1600 mg or most specifically from about 200 to 800 mg per treatment.
Treatment typically is administered one to three times daily. In another
embodiment, an effective amount of a compound of this invention is
between about 800 to 2400 mg/day.

[0083] Effective doses will also vary, as recognized by those skilled in
the art, depending on the diseases treated, the severity of the disease,
the route of administration, the sex, age and general health condition of
the patient, excipient usage, the possibility of co-usage with other
therapeutic treatments such as use of other agents and the judgment of
the treating physician. For example, guidance for selecting an effective
dose can be determined by reference to the prescribing information for
pirfenidone.

[0084] For pharmaceutical compositions that comprise a second therapeutic
agent, an effective amount of the second therapeutic agent is between
about 20% and 100% of the dosage normally utilized in a monotherapy
regime using just that agent. Preferably, an effective amount is between
about 70% and 100% of the normal monotherapeutic dose. The normal
monotherapeutic dosages of these second therapeutic agents are well known
in the art. See, e.g., Wells et al., eds., Pharmacotherapy Handbook, 2nd
Edition, Appleton and Lange, Stamford, Conn. (2000); PDR Pharmacopoeia,
Tarascon Pocket Pharmacopoeia 2000, Deluxe Edition, Tarascon Publishing,
Loma Linda, Calif. (2000), each of which references are incorporated
herein by reference in their entirety.

[0085] It is expected that some of the second therapeutic agents
referenced above will act synergistically with the compounds of this
invention. When this occurs, it will allow the effective dosage of the
second therapeutic agent and/or the compound of this invention to be
reduced from that required in a monotherapy. This has the advantage of
minimizing toxic side effects of either the second therapeutic agent or a
compound of this invention, synergistic improvements in efficacy,
improved ease of administration or use and/or reduced overall expense of
compound preparation or formulation.

[0086] In yet another embodiment the invention provides a pharmaceutical
composition comprising a compound of Formula I and a pharmaceutically
acceptable carrier, the administration of which to a test subject results
in a serum terminal elimination half-life of the compound that is greater
than the serum terminal elimination half-life of pirfenidone when
pirfenidone is administered to an equivalent test subject in a molar
equivalent pharmaceutical composition of pirfenidone under the same
dosing conditions as the compound of Formula I.

[0087] In other embodiments, the serum terminal elimination half-life of a
compound of Formula I is at least 110%, 120%, 130%, 140% or more of the
serum terminal elimination half-life of pirfenidone produced by
administration of a molar equivalent pirfenidone composition under the
same dosing conditions to an equivalent test subject. In a more specific
embodiment, the test subject is administered a single dose of the
composition comprising a compound of Formula I and a pharmaceutically
acceptable carrier and the equivalent test subject is administered a
single dose of the molar equivalent composition comprising pirfenidone
under the same dosing conditions. In an even more specific embodiment,
the test subject is the same individual as the equivalent test subject
and is simultaneously administered a single dose of a composition
comprising a compound of Formula I, a molar equivalent amount of
pirfenidone and a pharmaceutically acceptable carrier.

[0088] In a related embodiment, the invention provides a pharmaceutical
composition comprising a compound of Formula I and pharmaceutically
acceptable carrier, wherein the serum terminal elimination half-life of
the compound following IV administration of the composition to a test
subject is greater than 1.2 hours, greater than 1.4 hours, greater than
1.5 hours, greater than 2 hours, greater than 3 hours, or greater than
3.5 hours. In a more specific embodiment, the serum terminal elimination
half-life values are determined after administration of a single dose of
the composition.

[0089] In a related embodiment, the invention provides a pharmaceutical
composition comprising a compound of Formula I and a pharmaceutically
acceptable carrier, wherein the serum terminal elimination half-life of
the compound following administration of a single dose of the
pharmaceutical composition to a mammal, preferably a human, is greater
than the serum terminal elimination half-life of pirfenidone when
pirfenidone is administered to an equivalent test subject in a molar
equivalent pharmaceutical composition under the same dosing conditions as
the compound of Formula I.

[0090] In other embodiments, the serum terminal elimination half life of a
compound of Formula I produced by administration of a pharmaceutical
composition of this invention is greater than 2 hours, greater than 3
hours, or greater than 3.5 hours. In a more specific embodiment, the
compound of Formula I is administered in a single dose.

[0091] In another embodiment, the invention provides a pharmaceutical
composition comprising a compound of Formula I and a pharmaceutically
acceptable carrier, the administration of which to a test subject results
in an AUC0-∞ of the compound that is greater than the
AUC0-∞ of pirfenidone when pirfenidone is administered to an
equivalent test subject in a molar equivalent pharmaceutical composition
under the same dosing conditions as the compound of Formula I. In a more
specific embodiment, the test subject is administered a single dose of
the composition comprising a compound of Formula I and the equivalent
test subject is administered a single dose of the molar equivalent
composition comprising pirfenidone under the same dosing conditions. In
an even more specific embodiment, the test subject is the same individual
as the equivalent test subject and is simultaneously administered a
single dose of a composition comprising a compound of Formula I, a molar
equivalent amount of pirfenidone and a pharmaceutically acceptable
carrier.

[0092] In other embodiments, the AUC0-∞ produced by a
pharmaceutical composition of this invention is at least 110%, 120%,
130%, 140%, 150%, 160%, 170%, or more of the AUC0-∞ produced
by a molar equivalent pirfenidone composition administered under the same
dosing conditions. In a more specific embodiment, the AUC0-∞
values are determined after administration of a single dose of the
composition.

[0093] In another embodiment, the invention provides a pharmaceutical
composition comprising a compound of Formula I and a pharmaceutically
acceptable carrier, the oral administration of which to a test subject
results in a maximum serum concentration of the compound (Cmax) that
is greater than the maximum serum concentration of pirfenidone when
pirfenidone is orally administered to an equivalent test subject in a
molar equivalent pharmaceutical composition under the same dosing
conditions as the compound of Formula I. In a more specific embodiment,
the test subject is administered a single dose of the oral composition
comprising a compound of Formula I and the equivalent test subject is
administered a single dose of the molar equivalent oral composition
comprising pirfenidone under the same dosing conditions. In an even more
specific embodiment, the test subject is the same individual as the
equivalent test subject and is administered a single dose of an oral
composition comprising a compound of Formula I, a molar equivalent amount
of pirfenidone and a pharmaceutically acceptable carrier.

[0094] In a related embodiment, the maximum serum concentration a compound
of Formula I produced by oral administration of a pharmaceutical
composition of this invention is at least 120%, 130%, 140%, 150%, 160% or
more of the maximum serum concentration of pirfenidone produced by oral
administration of a molar equivalent pirfenidone composition administered
under the same dosing conditions. In a more specific embodiment, the
Cmax values are determined after administration of a single oral
dose of the composition.

[0095] The compounds of the present invention also demonstrate greater
resistance to certain metabolism as compared to pirfenidone. Thus, in
another embodiment, the invention provides a pharmaceutical composition
comprising a compound of Formula I and a pharmaceutically acceptable
carrier, wherein the rate of serum clearance of the compound following IV
dosing is less than the rate of serum clearance of pirfenidone following
intravenous administration of pirfenidone to an equivalent test subject
in a molar equivalent pharmaceutical composition and under the same
dosing conditions as the compound of Formula I. In other embodiments, the
rate of serum clearance of a compound following IV administration of a
composition of this invention is less than 90%, less than 80%, or less
than 70% of the serum clearance rate of pirfenidone following IV
administration of a molar equivalent pirfenidone composition to an
equivalent test subject administered under the same dosing conditions. In
a more specific embodiment, the test subject is administered a single
dose of the IV composition comprising a compound of Formula I and the
equivalent test subject is administered a single dose of the molar
equivalent IV composition comprising pirfenidone. In an even more
specific embodiment, the test subject is the same individual as the
equivalent test subject and is simultaneously administered a single dose
of an IV composition comprising a compound of Formula I, a molar
equivalent amount of pirfenidone and a pharmaceutically acceptable
carrier.

[0096] In a related embodiment, the invention provides a pharmaceutical
composition comprising a compound of Formula I and a pharmaceutically
acceptable carrier, wherein the rate of serum clearance of the compound
following IV administration of a single dose of the composition to a test
subject is about 200 to about 375, about 225 to about 350, or about 250
to about 325 ml/h/kg. In a more specific embodiment, the test subject is
a chimpanzee.

[0097] In yet another embodiment, the invention provides a pharmaceutical
composition comprising a compound of Formula I and a pharmaceutically
acceptable carrier, the administration of which to a test subject results
in at least one of: a) a similar steady state AUC0-∞; b) a
similar steady state Cmax; or c) a similar steady state Cmin
(minimum serum concentration of a compound) as compared to pirfenidone
when pirfenidone is administered to an equivalent test subject in a
pharmaceutical composition comprising an amount of pirfenidone that is
greater than the amount of the compound of Formula I on a mole basis of
active ingredient and that is administered under the same dosing
conditions as the compound of Formula I. In a more specific embodiment,
the test subject is administered a single dose of the IV composition
comprising a compound of Formula I and the equivalent test subject is
administered a single dose of the molar equivalent IV composition
comprising pirfenidone under the same dosing conditions. In an even more
specific embodiment, the test subject is the same individual as the
equivalent test subject and is simultaneously administered a single dose
of an IV composition comprising a compound of Formula I, a molar
equivalent amount of pirfenidone and a pharmaceutically acceptable
carrier.

[0098] In other embodiments, the effective amount of a compound of Formula
I required per day is no more than 80%, 70%, 60%, 50%, 40%, or less of
the amount of pirfenidone on a mole basis of active ingredient required
per day to produce a similar steady state AUC0-∞, a similar
steady state Cmax and/or a similar steady state Cmin when
administered under the same dosing conditions as the compound of Formula
I. In a more specific embodiment, the compound of Formula I is
administered once daily.

[0099] In a more specific embodiment, in each of the compositions set
forth above, the compound is selected from Compound 106 and Compound 108.

[0100] The term "molar equivalent amount" as used herein means an amount
present in a first composition that is the same as the amount present in
a second composition on a mole basis of active ingredient.

[0101] A "test subject" is any mammal, preferably a chimpanzee or a human.

[0102] An "equivalent test subject" is defined herein as being of the same
species and sex as the test subject, in the same fed/fasting state as the
test subject and which shows no more than 10% variability as compared to
the test subject in the pharmacokinetic parameter being tested after
administration of an equal amount of pirfenidone to both the test subject
and the equivalent subject. In certain embodiments, an "equivalent test
subject" is the same individual as the "test subject."

[0103] As used herein, "under the same dosing conditions" means that the
pharmaceutical compositions being compared contain the same carriers and
excipients and are administered using the same route and frequency.

[0104] As used herein, "similar steady state AUC0-∞" means that
the steady state AUC0-∞ values being compared are within 5% of
each other. For example, within 3%, such as within 2%.

[0105] As used herein, "similar steady state Cmax" means that the
steady state Cmax values being compared are within 5% of each other.
For example, within 3%, such as within 2%.

[0106] As used herein, "similar steady state Cmin" means that the
steady state Cmin values being compared are within 5% of each other.
For example, within 3%, such as within 2%.

Methods of Treatment

[0107] In another embodiment, the invention provides a method of
inhibiting the production and activity of TNF-alpha and TGF-beta in a
cell, comprising contacting a cell with one or more compounds of Formula
I herein.

[0108] According to another embodiment, the invention provides a method of
treating a disease that is beneficially treated by pirfenidone in a
patient in need thereof comprising the step of administering to said
patient an effective amount of a compound or a composition of this
invention. Such diseases are well known in the art and are disclosed in,
but not limited to the following patents and published applications: WO
2001058448, WO 2003051388, WO 2004019863, WO 2004073713, WO 2004105684,
WO 2005039598, WO 2005038056, WO 2005110478, and WO 2007053610.

[0110] In one particular embodiment, the method of this invention is used
to treat a disease or condition selected from idiopathic pulmonary
fibrosis, neurofibromatosis, Hermansky-Pudlak syndrome, diabetic
nephropathy, renal failure, hypertrophic cardiomyopathy (HCM),
glomerulosclerosis (FSGS), radiation-induced fibrosis, multiple
sclerosis, and uterine leiomyomas (fibroids) in a patient in need
thereof.

[0111] In another particular embodiment, the method of the invention is
used to treat renal fibrosis, hepatic fibrosis, uterine leiomyomas,
keloid scarring, multiple sclerosis, radiation-associated fibrosis, organ
transplant rejection, or cancer in a patient in need thereof.

[0112] In still another particular embodiment, the method of this
invention is used to treat idiopathic pulmonary fibrosis in a patient in
need thereof. In one aspect of this embodiment, the amount of the
compound of this invention administered to the patient is from about 900
to about 1750 mg/day.

[0113] In another particular embodiment, the method of this invention is
used to treat secondary progressive multiple sclerosis in a patient in
need thereof. In one aspect of this embodiment, the amount of the
compound of this invention administered to the patient is in the range of
from about 900 to about 2350 mg/day.

[0114] In another particular embodiment, the method of this invention is
used to treat pancreatic cancer in a patient in need thereof.

[0115] In another more particular embodiment, the method of this invention
is used to treat renal fibrosis in a patient in need thereof. More
particularly the method is used to treat renal fibrosis as the result of
diabetic nephropathy, glomerulopathy/FSGS or hypertension-related
nephropathy. In one aspect of this embodiment, the amount of the compound
of this invention administered to the patient is from about 900 to about
2350 mg/day.

[0116] In another embodiment, the amount of the compound of this invention
administered to treat radiation fibrosis in a patient in need thereof is
from about 900 to about 2350 mg/day.

[0117] In still another embodiment, the amount of the compound of this
invention administered to treat hepatic fibrosis in a patient in need
thereof is in the range of from 600 to about 1150 mg/day.

[0118] Methods delineated herein also include those wherein the patient is
identified as in need of a particular stated treatment. Identifying a
patient in need of such treatment can be in the judgment of a patient or
a health care professional and can be subjective (e.g. opinion) or
objective (e.g. measurable by a test or diagnostic method).

[0119] In another embodiment, any of the above methods of treatment
comprises the further step of co-administering to said patient one or
more second therapeutic agents. The choice of second therapeutic agent
may be made from any second therapeutic agent known to be useful for
co-administration with pirfenidone. The choice of second therapeutic
agent is also dependent upon the particular disease or condition to be
treated. Examples of second therapeutic agents that may be employed in
the methods of this invention are those set forth above for use in
combination compositions comprising a compound of this invention and a
second therapeutic agent.

[0120] The term "co-administered" as used herein means that the second
therapeutic agent may be administered together with a compound of this
invention as part of a single dosage form (such as a composition of this
invention comprising a compound of the invention and an second
therapeutic agent as described above) or as separate, multiple dosage
forms. Alternatively, the additional agent may be administered prior to,
consecutively with, or following the administration of a compound of this
invention. In such combination therapy treatment, both the compounds of
this invention and the second therapeutic agent(s) are administered by
conventional methods. The administration of a composition of this
invention, comprising both a compound of the invention and a second
therapeutic agent, to a patient does not preclude the separate
administration of that same therapeutic agent, any other second
therapeutic agent or any compound of this invention to said patient at
another time during a course of treatment.

[0121] Effective amounts of these second therapeutic agents are well known
to those skilled in the art and guidance for dosing may be found in
patents and published patent applications referenced herein, as well as
in Wells et al., eds., Pharmacotherapy Handbook, 2nd Edition, Appleton
and Lange, Stamford, Conn. (2000); PDR Pharmacopoeia, Tarascon Pocket
Pharmacopoeia 2000, Deluxe Edition, Tarascon Publishing, Loma Linda,
Calif. (2000), and other medical texts. However, it is well within the
skilled artisan's purview to determine the second therapeutic agent's
optimal effective-amount range.

[0122] In one embodiment of the invention, where a second therapeutic
agent is administered to a subject, the effective amount of the compound
of this invention is less than its effective amount would be where the
second therapeutic agent is not administered. In another embodiment, the
effective amount of the second therapeutic agent is less than its
effective amount would be where the compound of this invention is not
administered. In this way, undesired side effects associated with high
doses of either agent may be minimized. Other potential advantages
(including without limitation improved dosing regimens and/or reduced
drug cost) will be apparent to those of skill in the art.

[0123] In yet another aspect, the invention provides the use of a compound
of Formula I alone or together with one or more of the above-described
second therapeutic agents in the manufacture of a medicament, either as a
single composition or as separate dosage forms, for treatment or
prevention in a patient of a disease, disorder or symptom set forth
above. Another aspect of the invention is a compound of Formula I for use
in the treatment or prevention in a patient of a disease, disorder or
symptom thereof delineated herein.

Diagnostic Methods and Kits

[0124] The compounds and compositions of this invention are also useful as
reagents in methods for determining the concentration of pirfenidone in
solution or biological sample such as plasma, examining the metabolism of
pirfenidone and other analytical studies.

[0125] According to one embodiment, the invention provides a method of
determining the concentration, in a solution or a biological sample, of
pirfenidone, comprising the steps of: [0126] a) adding a known
concentration of a compound of Formula I to the solution of biological
sample; [0127] b) subjecting the solution or biological sample to a
measuring device that distinguishes pirfenidone from a compound of
Formula I; [0128] c) calibrating the measuring device to correlate the
detected quantity of the compound of Formula I with the known
concentration of the compound of Formula I added to the biological sample
or solution; and [0129] d) measuring the quantity of pirfenidone in the
biological sample with said calibrated measuring device; and [0130] e)
determining the concentration of pirfenidone in the solution of sample
using the correlation between detected quantity and concentration
obtained for a compound of Formula I.

[0131] Measuring devices that can distinguish pirfenidone from the
corresponding compound of Formula I include any measuring device that can
distinguish between two compounds that differ from one another only in
isotopic abundance. Exemplary measuring devices include a mass
spectrometer, NMR spectrometer, or IR spectrometer.

[0132] In another embodiment, the invention provides a method of
evaluating the metabolic stability of a compound of Formula I comprising
the steps of contacting the compound of Formula I with a metabolizing
enzyme source for a period of time and comparing the amount of the
compound of Formula I with the metabolic products of the compound of
Formula I after the period of time.

[0133] In a related embodiment, the invention provides a method of
evaluating the metabolic stability of a compound of Formula I in a
patient following administration of the compound of Formula I. This
method comprises the steps of obtaining a serum, urine or feces sample
from the patient at a period of time following the administration of the
compound of Formula I to the subject; and comparing the amount of the
compound of Formula I with the metabolic products of the compound of
Formula I in the serum, urine or feces sample.

[0134] The present invention also provides kits for use to treat
idiopathic pulmonary fibrosis, neurofibromatosis, Hermansky-Pudlak
syndrome, diabetic nephropathy, renal fibrosis, hepatic fibrosis, keloid
scarring, hypertrophic cardiomyopathy (HCM), glomerulosclerosis (FSGS),
radiation-induced fibrosis, multiple sclerosis, organ rejection, cancer,
and uterine leiomyomas (fibroids). These kits comprise (a) a
pharmaceutical composition comprising a compound of Formula I or a salt,
hydrate, or solvate thereof, wherein said pharmaceutical composition is
in a container; and (b) instructions describing a method of using the
pharmaceutical composition to treat one or more of the aforementioned
disease or conditions.

[0135] The container may be any vessel or other sealed or sealable
apparatus that can hold said pharmaceutical composition. Examples include
bottles, ampules, divided or multi-chambered holders bottles, wherein
each division or chamber comprises a single dose of said composition, a
divided foil packet wherein each division comprises a single dose of said
composition, or a dispenser that dispenses single doses of said
composition. The container can be in any conventional shape or form as
known in the art which is made of a pharmaceutically acceptable material,
for example a paper or cardboard box, a glass or plastic bottle or jar, a
re-sealable bag (for example, to hold a "refill" of tablets for placement
into a different container), or a blister pack with individual doses for
pressing out of the pack according to a therapeutic schedule. The
container employed can depend on the exact dosage form involved, for
example a conventional cardboard box would not generally be used to hold
a liquid suspension. It is feasible that more than one container can be
used together in a single package to market a single dosage form. For
example, tablets may be contained in a bottle, which is in turn contained
within a box. In one embodiment, the container is a blister pack.

[0136] The kits of this invention may also comprise a device to administer
or to measure out a unit dose of the pharmaceutical composition. Such
device may include an inhaler if said composition is an inhalable
composition; a syringe and needle if said composition is an injectable
composition; a syringe, spoon, pump, or a vessel with or without volume
markings if said composition is an oral liquid composition; or any other
measuring or delivery device appropriate to the dosage formulation of the
composition present in the kit.

[0137] In certain embodiment, the kits of this invention may comprise in a
separate vessel of container a pharmaceutical composition comprising a
second therapeutic agent, such as one of those listed above for use for
co-administration with a compound of this invention.

[0138] The invention now being generally described, it will be more
readily understood by reference to the following examples which are
included merely for purposes of illustration of certain aspects and
embodiments of the present invention, and are not intended to limit the
invention in any way.

[0140] To a microwave reactor vial was added pirfenidone (20 mg, 0.108
mmol), 35% w/w DCl in D2O (Aldrich, 99 atom % D, 1.25 mL), and a
stirbar. The vial was sealed and the clear colorless solution was heated
in a Biotage Personal Chemistry microwave reactor for 30 min at
170° C. The vial was cooled to room temperature (rt) and the
reaction mixture was transferred to a separatory funnel. The mixture was
diluted with water and CH2Cl2. The acidic aqueous layer was
neutralized via the careful addition of 5N aqueous NaOH. The layers were
shaken and separated. The aqueous layer was extracted with
CH2Cl2 and the organic layers were combined, washed with brine,
dried over magnesium sulfate, filtered and concentrated on a rotary
evaporator to yield the title compound as a clear colorless residue.
1H NMR (300 MHz, CDCl3) δ 2.11 (s, 3H), 7.12 (m, 1H),
7.28 (m, 1H), 7.36-7.50 (m, 5H). LCMS m/z 186.9 [M+H]. 1H NMR
integration indicated the presence of hydrogen at the R1 position as
0.1% relative to the protio compound.

Example 3

3,6-Dideutero-5-(methyl-d3)-1-phenylpyridin-2(1H)-one (Compound 106)

##STR00011##

[0141] To a thick-walled glass pressure vessel flushed with nitrogen was
added pirfenidone (100 mg, 0.540 mmol), D2O (Cambridge Isotopes,
99.9 atom % D, 1.2 mL), and a stir bar. To the stirring slurry was then
added 35% w/w DCl in D2O (Aldrich, 99 atom % D, 0.135 mL, 1.64 mmol)
and the solids began to partially dissolve. To the mixture was added 10%
palladium on carbon (10 mg, 10% w/w of pirfenidone) and the vessel was
flushed once more with nitrogen. The vessel was then flushed with
hydrogen and sealed. The vessel was heated in a 160° C. oil bath
for 16.5 hours with stirring (this reaction time varies with reaction
scale). The vessel was cooled to rt and flushed with nitrogen. The
reaction mixture was diluted with CH2Cl2 (25 mL), stirred
vigorously, and filtered through a 0.45 micron syringe filter. The
palladium residue in the filter was flushed with CH2Cl2 (50 mL)
and the combined filtrate bilayer was poured into a separatory funnel.
Saturated aqueous sodium bicarbonate (50 mL) was added and the layers
were shaken and separated. The organic layer was washed with brine, dried
over magnesium sulfate, filtered and concentrated on a rotary evaporator
to afford the title compound as a clear, colorless residue (57 mg). The
residue solidified upon standing. 1H NMR (300 MHz, CDCl3)
δ 7.26 (s, 1H), 7.36-7.50 (m, 5H). 1H NMR (300 MHz,
THF-d8) δ 7.20 (s, 1H), 7.30-7.43 (m, 5H). LCMS m/z 191.0
[M+H]. This method produced batches of Compound 106 for which 1H NMR
integration indicated the presence of hydrogen at the methyl group as
15%-26% relative to the protio compound; at the R1 position as 2%-7%
relative to the protio compound; and at the R3 position as 5%-12%
relative to the protio compound.

Example 4

5-(Methyl-d3)-1-phenylpyridin-2(1H)-one (Compound 108)

##STR00012##

[0143] Compound 108 was synthesized according to Scheme 5, above. Details
of the synthesis are set forth below.

Step 1. 5-Methyl-d3)-pyridin-2(1H)-one (18)

[0144] To a round-bottom flask was added commercially-available
6-oxo-1,6-dihydropyridine-3-carbonitrile (17, 1.00 g, 8.33 mmol), sodium
dodecylsulfate ("SDS", 240 mg, 0.833 mmol), and 10% palladium on carbon
(300 mg). Water (20.8 mL), n-butanol (20.8 mL), and 10% aqueous
H2SO4 (4.43 mL, 8.33 mmol) were added with stirring. The vessel
was flushed first with nitrogen, then with deuterium gas (Aldrich, 99.9
atom % D). The reaction was stirred at rt under a balloon of deuterium
gas for 2-3 days. The vessel was flushed with nitrogen, the slurry was
filtered and the palladium residue was washed well with n-butanol. The
filtrate was transferred to a separatory funnel and the layers were
shaken and separated. The aqueous layer was adjusted to approximately
pH=5 via careful addition of 1N aqueous NaOH. The organic and aqueous
layers were recombined in the separatory funnel, shaken, and separated.
The aqueous layer was extracted with n-butanol (2×25 mL) and the
combined organic layers were concentrated on a rotary evaporator to a
minimum volume of residue. The material was diluted with 5% methanol in
dichloromethane, filtered through a short silica plug and eluted with 5%
methanol in dichloromethane. The product fractions were purified via
column chromatography on an ISCO instrument (0% to 5% methanol in
dichloromethane) to afford 303 mg of 18. 1H NMR (300 MHz,
CDCl3) δ 6.53 (d, J=9.3, 1H), 7.14 (d, J=2.5, 1H), 7.33 (dd,
J=2.3, 9.1, 1H), 13.10 (br s, 1H). LCMS m/z 113.2 [M+H].

[0147] To a round-bottom flask were added
5-(methyl-d3)-pyridin-2(1H)-one (18, 0.522 g, 4.65 mmol, prepared as
shown in Example 6, below), K3PO4 (1.98 g, 9.31 mmol), and CuI
(177 mg, 0.931 mmol) under N2. Toluene (7.8 mL) was added with
stirring. Iodobenzene-d5 (CDN Isotopes, 99.7 atom % D, 0.613 mL,
5.59 mmol) was added, followed by N,N-dimethylethylenediamine (0.201 mL,
1.86 mmol). The heterogeneous reaction mixture was heated to reflux for 3
h. The mixture was then cooled to 75° C. and filtered through a
pad of Celite. The filter cake was washed twice with hot (75° C.)
toluene. The filtrate was transferred to a separatory funnel, and washed
with water (3×). The combined aqueous layers were extracted with
toluene (2×). The combined organic layers were washed with water
(1×), aq. 1N HCl (1×) and water (1×). The combined
organic layers were dried (Na2SO4) and concentrated to dryness.
To the resulting yellow solid was added heptane (15 mL) and the mixture
was stirred at room temperature for 48 h. The mixture was filtered and
the filtrate dried under vacuum to afford 414 mg (46%) of Compound 109 as
a white solid. 1H NMR (300 MHz, DMSO-d6) δ 7.48 (dd,
J=0.6, 2.6, 1H), 7.43 (dd, J=2.6, 9.4, 1H), 6.46 (dd, J=0.8, 9.3, 1H).
LCMS m/z 194.2 [M+H]. A signal corresponding to the protio methyl group
was not detected in the 1H NMR. A signal corresponding to the protio
phenyl group was not detected in the 1H NMR.

[0148] An alternative synthesis of 5-(methyl-d3)-pyridin-2(1H)-one
(18) and 5-(methyl-d3)-1-phenylpyridin-2(1H)-one (Compound 108) is
depicted in Scheme 6 and described below.

##STR00014##

Step 1. 5-(Methyl-d3)-pyridin-2(1H)-one (18)

[0149] To a 2000 mL, 4-neck round bottom flask equipped with a mechanical
stirrer, a thermocouple, and an addition funnel was added
5-bromo-2-methoxy-pyridine (19, 84.11 mL; 1 equiv), followed by t-BuOMe
(1050 mL). The resulting mixture was stirred under N2 and cooled to
-39° C. using a dry-ice/acetone bath. n-BuLi was then added as a
2.5 M solution in hexane (286 mL; 1.1 equiv) via addition funnel. The
addition rate was adjusted to keep the internal temperature below
-30° C. The total addition time was 25 min. The resulting orange
slurry was stirred for 80 min while maintaining the reaction temperature
between -40° C. and -30° C. A solution of
iodomethane-d3 (46.5 mL; 1.15 equiv; Isotech, 99.5+ atom % D) in
t-BuOMe (126 mL) was then added via syringe at -39° C. The
addition rate was adjusted to keep the internal temperature below
-28° C. The total addition time was 60 min. The resulting slurry
was stirred for 80 min while maintaining the reaction temperature between
-40° C. and -30° C. The cold bath was then removed, and the
reaction mixture was allowed to warm to 15° C. over a period of 65
min. This produced an orange slurry comprising
5-(methyl-d3)-2-methoxypyridine 20, which was not purified prior to
the next step as described below.

[0150] The orange slurry containing 5-(methyl-d3)-2-methoxypyridine
20 was filtered through a pad of Celite pre-wetted with t-BuOMe. The
flask was rinsed with t-BuOMe (2×125 mL). The rinses were used to
further wash the Celite cake. The yellow filtrate was transferred to a 2
L separatory funnel and then was washed with aqueous 6 N HCl (3×475
mL and 2×250 mL). The combined aqueous layers were then washed with
heptane (3×250 mL). The aqueous layer was transferred to a 2 L,
3-neck round bottom flask equipped with a magnetic stirrer, thermocouple
and a condenser. The aqueous layer was heated to reflux (109° C.)
for 25 h, and then was allowed to cool to rt overnight. An aliquot was
sampled and analyzed by HPLC to show clean transformation with a product
conversion rate of 98.7% by HPLC. The aqueous layer was then cooled to
5° C. in an ice bath and was neutralized with 50 w/w % aq. NaOH
while keeping the internal temperature below 30° C. The pH change
was monitored using a pH meter. Neutralization was completed when the pH
was 7.02. The total amount of 50 w/w % aq. NaOH used was less than
approximately 390 g.

[0151] The neutralized solution was then filtered through a pad of
water-wetted Celite to remove a minor amount of a dark brown solid. The
filtrate which was obtained was yellow. Vacuum suction was used to dry
the wet Celite cake. The pH of the filtrate was readjusted to 7.02 using
aqueous 1 N HCl. Most of the remaining water was removed under vacuum
(50-70 mm Hg) at 70° C. The residue became saturated with NaCl
when 900 mL water was removed, and the remaining water volume was about
400 mL. The aqueous solution was then decanted into a 2 L separatory
funnel, while the solid residue was washed with CH2Cl2 (300
mL). The CH2Cl2 layer was also transferred to the separatory
funnel. The aqueous layer that was remaining in the separatory funnel was
extracted with the CH2Cl2. This solid wash with
CH2Cl2 and extraction was repeated 5 more times. The combined
organic layer (total volume=1.8 L) was washed with water (250 mL). The
phase separation was observed to be slow. The lower organic layer was
cloudy and became clear after standing overnight. The organic layer was
collected and concentrated in vacuo to dryness to obtain 53.25 g of the
crude product as a light yellow solid ("Crop 1").

[0152] The aqueous layers were combined and concentrated in vacuo to
dryness (50-70 mmHg, 70° C.) to obtain a solid residue. The
residue was taken up in CH2Cl2 (300 mL) and stirred for 30 min.
The mixture was filtered through a core-porosity funnel to obtain a clear
filtrate, which was concentrated in vacuo to dryness to obtain 19.87 g of
additional product as a yellow solid ("Crop 2").

[0153] The two crops of product were analyzed by HPLC to show that Crop 1
had a product purity of 93.5% and Crop 2 had a product purity=99.7%. The
two crops were then combined and added to a 3-neck, 1 L round bottom
flask equipped with mechanical stirrer, thermocouple, and a condenser.
t-BuOMe (400 mL) and CH2Cl2 (100 mL) were added and the
resulting mixture was heated to reflux (54° C.) under N2 for
3.5 hours, then cooled to rt while maintaining stirring over the weekend.
The resulting slurry was filtered through a core-porosity funnel and the
solid was washed with t-BuOMe (100 mL) and then air-dried to obtain 63.92
g of the product as a light tan solid with an HPLC purity of 98.5%.

[0154] The filtrate was then concentrated in vacuo to dryness to afford
8.35 g of additional product as a yellow residue with an HPLC purity of
51%.

[0155] The light tan product solid was transferred to a 1 L Erlenmeyer
flask, and toluene (625 mL) was added. The mixture was heated to reflux
to dissolve the solid. The mixture was then gradually cooled to ambient
temperature and then to 10° C. in an ice bath. The mixture was
then filtered through a core-porosity funnel. The solid was washed with
t-BuOMe (2×50 mL) and air-dried under vacuum to afford 57.07 g of
the product as a light tan solid. Analysis: 1H NMR (400 MHz) showed
no aliphatic peaks corresponding to 5-CHxD3-x-2-pyridone (where
x=1, 2, or 3). Deuterium incorporation >99%, as defined by deuterium
purity of CD3I. Chemical purity by HPLC=99.1%.

[0157] The reaction mixture was removed from the heating mantle, cooled to
75° C., and then filtered through a pad of Celite pre-wetted with
toluene. The collected wet cake was washed with hot toluene (75°
C., 2×125 mL). Residual liquid was removed from the wet cake with
vacuum suction. A blue residue remained on the filter cake. The residue
and the filter cake were retained.

[0158] The filtrate was then transferred to a 2 L separatory funnel and
washed with water (3×250 mL). The combined aqueous layers were
extracted with toluene (2×150 mL). The remaining aqueous layer was
dark blue in color and was retained for further extraction. The combined
toluene layers were then washed with water (300 mL), aqueous 1 N HCl (300
mL) and water (300 mL). The first water wash showed a light blue color in
the aqueous layer. The diluted acid wash showed a light brown color in
the aqueous layer. The last water wash was nearly colorless in the
aqueous layer. These two light blue and colorless water layers were
retained for further extraction. The toluene layer was concentrated in
vacuo to near dryness, leaving a light yellow solid. Heptane (500 mL) was
added to this solid, and the resulting mixture was stirred at rt under
N2 overnight. The mixture was filtered, then air dried under vacuum
to afford 60.3 g of a white solid ("First Batch") which was found to be
99.4% pure by HPLC.

[0159] The retained dark blue aqueous layer was then back extracted with
CH2Cl2 (2×125 mL) to obtain additional crude product.
Although both liquid phases were very dark in color, there was a
discernable separation line between them. The retained light blue and
colorless water layers were also extracted with CH2Cl2 (125 mL
for each). The combined CH2Cl2 layers were washed with water
(3×150 mL), aqueous 1N HCl (200 mL) and water (150 mL). A greenish
color present in the CH2Cl2 layer disappeared after these water
washes. The CH2Cl2 layer was then concentrated in vacuo to
afford 11.91 g of a light brown oil that solidified quickly upon standing
("Second Batch").

[0160] Residual product was then collected from the blue residue on the
wet filter cake. The blue residue was transferred back to the reaction
flask. Water (700 mL) and toluene (500 mL) were added. The resulting
mixture was stirred mechanically for 40 min, and then was filtered
through the same Celite cake. Both the flask and the Celite cake were
washed with toluene (2×100 mL). The resulting dark-blue toluene
filtrate was transferred to the separatory funnel and was washed with
water (300 mL), aqueous 1 N HCl (300 mL) and water (300 mL). The toluene
was removed in vacuo to afford 4.14 g of a yellow solid ("Third Batch").

[0161] The combined second and third batches of solid were then
transferred to a 1 L round bottom flask and heptane (300 mL) was added.
The resulting mixture was stirred vigorously at rt under N2
overnight and then was filtered to provide 15.2 g of the product ("Fourth
Batch") as a cream-white solid with an HPLC purity profile of 99.1%.

[0162] The first and fourth batches of solid were combined, taken up in
heptane (350 mL), and then filtered. The solid was dried under vacuum to
provide the product (Compound 108) as a white solid, weight (74.31 g,
80.5% yield) with a purity of 99.65% by HPLC. A signal corresponding to
the protio methyl group was not detected in the 1H NMR (400 MHz).

Example 7

Synthesis and Isolation of 5-(methyl-d3)-2-methoxypyridine (20)

[0163] In order to obtain isolated 5-(methyl-d3)-2-methoxypyridine
20, the first step of Scheme 6 was modified as follows.

[0164] To a 100 mL round-bottom flask equipped with a magnetic stirrer and
thermocouple was added 5-bromo-2-methoxy-pyridine (5.83 g, 31 mmol, 1 eq)
and t-BuOMe (50 mL). The solution was cooled to -40° C. An n-BuLi
solution (21.31 mL, 1.6 M in hexane, 34.1 mmol, 1.1 eq) was then added
via a syringe. The addition rate was adjusted to keep the internal
temperature below -30° C. The solution was added over a period of
25 min. After the addition finished, the mixture was stirred at between
-40° C. and -35° C. for 90 min. The resulting light pink
slurry in t-BuOMe (5 mL) was passed through a small pad of dry
K2CO3. To the pinkish reaction mixture was then added
iodomethane-d3 (Isotech, 99.5+ atom % D) (5.17 g, 35.65 mmol, 1.15
eq.) via a syringe, at an addition rate to keep the internal temperature
below -30° C. Addition time was 25 min. After the addition, the
slurry was stirred at -30° C. for 30 min, then was warmed to
0° C., followed by addition of water (40 mL) and additional
stirring for 25 min. The solution was then transferred to a separatory
funnel and the aqueous layer was discarded. The organic layer was washed
with 1N HCl (50 mL), and the organic layer was discarded. The remaining
acidic aqueous layer was washed with t-BuOMe (2×25 mL), then with
1N NaOH (55 mL), and was then extracted into t-BuOMe (3×30 mL). The
resulting organic layer was collected and washed with water (2×30
mL). The resulting organic layer was concentrated in vacuo to yield 3.0 g
(77%) of 5-(methyl-d3)-2-methoxypyridine 20 as a light yellow
liquid. 1H NMR (400 MHz, CDCl3): 7.96 (1H, d, J=2.38 Hz), 7.38
(1H, dd, J=2.42 Hz, 8.38 Hz), 6.66 (1H, d=8.41 Hz), 3.90 (s, 3H). A
signal corresponding to the protio methyl group was not detected in the
1H NMR.

[0166] The objectives of this study were to determine the metabolic
stability of Compound 106 as compared to pirfenidone in pooled human
liver microsomal incubations. Samples of the test compounds, exposed to
pooled human liver microsomes, were analyzed using LC-MS/MS detection
with multiple reaction monitoring (MRM) to measure the disappearance of
the test compounds.

[0167] Human liver microsomes were obtained from XenoTech, LLC (Lenexa,
Kans.). The incubation mixtures were prepared according to Table 2:

[0168] The reaction mixture of Table 2 was prepared. Two aliquots of this
reaction mixture were used for test compound 106. The aliquots were
incubated in a shaking water bath at 37° C. for 3 minutes. Test
compound 106 was then added into each aliquot at a final concentration of
0.5 μM. The reaction was initiated by the addition of cofactor (NADPH)
into one aliquot (the other aliquot (no NADPH) serving as the negative
control). Both aliquots were then incubated in a shaking water bath at
37° C. Fifty microliters (50 μL) of the incubation mixtures
were withdrawn in triplicate from each aliquot at multiple time points
and combined with 50 μl, of ice-cold acetonitrile to terminate the
reaction. The same procedure was followed for pirfenidone and the
positive control, 7-ethoxy coumarin. Testing was done in triplicate.

[0169] All samples were analyzed using LC-MS/MS. Surprisingly, both
pirfenidone and Compound 106 were very stable in human liver microsomes.
After 30 minutes of exposure, greater than 75% of each compound remained
unmetabolized.

Example 9

Pharmacokinetics of Compound 106 after Intravenous and Oral Dosing in Rats

[0170] Male Sprague-Dawley rats (3 for each route of administration) were
administered a combination of 8 mg/kg of Compound 106 and 8 mg/kg of
pirfenidone in 10% DMI (dimethyl isosorbide), 15% ethanol, 35% PG in
distilled water by either oral or intravenous dosing. Blood samples from
the dosed rats were collected prior to dosing and at 15, 30, 45, 60, 75,
90, 120, 240, and 360 minutes post-dosing. Plasma was isolated and
prepared for analysis by mixing 0.1 ml of plasma in an Eppendorf tube
with 20 μL methanol and 500 μL of quetiapine (50 ng/ml as an
internal standard), vortexing for 1 minute and then centrifuging at
15,000 rpm for 5 minutes to remove any cellular debris. Plasma samples
were analyzed by LC-MS/MS.

[0171] LC was performed using an Agilent (Agilent Technologies Inc. USA)
liquid chromatograph equipped with an isocratic pump (1100 series), an
autosampler (1100 series) and a degasser (1100 series). Plasma samples (2
μL) were run at 25° C. on a Phenomenex Gemini, C18, 5 μm,
(50 mm×2.0 mm) column using 0.1% formic acid:methanol (30:70) as
the mobile phase with an elution rate of 300 μL/min.

[0172] Mass spectrometric analysis was performed on plasma samples (2
μL) prepared as set forth above using an API3000 (triple-quadrupole)
instrument from AB Inc (Canada) with an ESI interface. The data
acquisition and control system were created using Analyst 1.4 software
from ABI Inc.

[0173] The results of the above assay are shown in FIG. 1 and FIG. 2 and
are summarized in Table 3, below.

Compound 106 showed a 62% increase in half-life and a 72% increase in AUC
as compared to pirfenidone following intravenous administration in rats.
A similar effect was observed after oral dosing where Compound 106 showed
a 75% increase in AUC as compared to pirfenidone.

Example 10

Pharmacokinetics of Compounds 106 and 108 after Intravenous and Oral
Dosing in Chimpanzees

[0174] Chimpanzees (one male and one female for each route of
administration) were administered a combination of 100 mg of Compound
106, 100 mg of Compound 108 and 100 mg of pirfenidone in 10% DMI
(dimethyl isosorbide), 15% ethanol, 35% PG in distilled water (total
volume 150 ml) by either oral or intravenous dosing. Intravenous dosing
was performed by infusion over a 30 minute period. Blood samples from the
orally dosed chimps were collected just prior to dosing and at 15, 30,
60, 90, 120, 240, 360, 480, 600, 720 and 1440 minutes post-dosing. Blood
samples (4.5 ml) from the intravenously dosed chimps were collected just
prior to infusion, at 15 and 29.5 minutes after the start of infusion,
and then at 6, 15, 30, 45, 60, 120, 240, 360, 480, 600, 720 and 1440
minutes post-infusion. Plasma was isolated and prepared for analysis by
mixing 0.1 ml of plasma with 300 μL of indiplon in (50 ng/ml in
acetonitrile/water; 90/10; v/v) as an internal standard, vortexing and
then centrifuging to remove any precipitated protein.

[0175] Plasma samples (10 μl) were injected to a Zorbax SB-C8 (Rapid
Resolution) column (2.1×30 mm, 3.5 μm). The initial mobile phase
condition was 100% A (water with 0.1% formic acid) and 0% B (acetonitrile
with 0.1% formic acid) with a flow rate at 0.75 mL/min. Mobile phase B
was allowed to reach 100% in 0.75 minutes and held for 1.0 minute before
ramping back to 0% in another 0.1 minute. The overall run time was 3
minutes. The precursor/product ion pairs were set at m/z 186/92, m/z
191/97, m/z 189/95 and m/z 377/293 for detecting pirfenidone, Compound
106, Compound 108 and indiplon, respectively. Plasma concentration data
for each compound in each animal was individually fitted to a
2-compartment model using WinNonLin version 5.2 (PK Model #9) with
weighting of 1/y.

[0176] The results of the above assay are shown in FIG. 3 and FIG. 4 and
are summarized in Table 4 below.

Compound 106 showed a greater than 10% increase in half-life, an almost
50% increase in AUC and a greater than 30% decrease in clearance rate as
compared to pirfenidone following intravenous administration in chimps.
Compound 108 also showed similar effects demonstrating a greater than 20%
increase in half-life, an almost 50% increase in AUC and a greater than
30% decrease in clearance rate as compared to pirfenidone following
intravenous administration in chimps.

[0177] Similar effects for the compounds of this invention were observed
after oral dosing. Compound 106 showed a greater than 50% increase in AUC
and Cmax as compared to pirfenidone. Compound 108 demonstrated an
almost 60% increase in AUC and Cmax as compared to pirfenidone.

Example 11

Pharmacokinetics of Compound 108 and 109 after Intravenous and Oral Dosing
in Rats

[0178] Male Sprague-Dawley rats (3 for each route of administration) were
administered a combination of a) 8 mg/kg of Compound 109 and 8 mg/kg of
pirfenidone; b) a combination of 8 mg/kg of Compound 108 and 8 mg/kg of
pirfenidone; or c) a combination of 8 mg/kg of Compound 108 and 8 mg/kg
of Compound 109 in 10% DMI (dimethyl isosorbide), 15% ethanol, 35% PG in
distilled water by either oral or intravenous dosing. For all dosings,
each compound was dissolved in 5% glucose containing 10% DMI (dimethyl
isosorbide), 15% ethanol, and 35% PG in distilled water.

[0179] Dosing, blood sampling, plasma preparation and serum analyses were
as described in Example 9. The results of these studies for combinations
a) and b) above are shown in FIGS. 5 through 8, and in Table 5, below.

[0180] The data demonstrates that both Compound 108 and Compound 109
demonstrate a greater serum half-life and AUC0-∞, and a
reduced rate of clearance following intravenous dosing as compared to
pirfenidone. In addition both Compound 108 and Compound 109 demonstrate a
greater Cmax and oral bioavailability following oral dosing as
compared to pirfenidone.

[0181] Without further description, it is believed that one of ordinary
skill in the art can, using the preceding description and the
illustrative examples, make and utilize the compounds of the present
invention and practice the claimed methods. It should be understood that
the foregoing discussion and examples merely present a detailed
description of certain preferred embodiments. It will be apparent to
those of ordinary skill in the art that various modifications and
equivalents can be made without departing from the spirit and scope of
the invention. All the patents, journal articles and other documents
discussed or cited above are herein incorporated by reference.